Drug dispensing components

ABSTRACT

A medicament dispenser comprising a canister and a drug dispensing valve, wherein one or more surfaces of said canister and/or valve has a fluorinated coating provided by a process comprising generating one or more fluorine-containing radical species and polymerising said radicals on said one or more surfaces, provided that the radicals are generated by a hot filament chemical vapour process, pyrolisation of fluoroparylene dimers, use of a photo initiator to create radicals from a fluoroacrylate or laser ablation of a fluoropolymer target. Also disclosed is a medicament dispenser comprising a canister and a drug-dispensing valve, wherein one or more surfaces of said canister and/or valve has a fluorinated coating provided by a process comprising incorporating a fluorine-containing species into a liquid or gas, depositing a fluorine-containing layer on said one or more surfaces, and thereafter optionally removing the liquid or gas.

RELATED APPLICATIONS

The present application claims priority from UK patent application No.0122725.5 filed 21 Sep. 2001, the entire content of which is herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to medicament dispensers, metered doseinhalers and components thereof. More especially, the invention relatesto medicament dispensers and metered dose inhalers for consistentlydispensing a prescribed dose of medicament.

BACKGROUND TO THE INVENTION

Drugs for treating respiratory and nasal disorders are frequentlyadministered in aerosol formulations through the mouth or nose. Onewidely used method for dispensing such aerosol drug formulationsinvolves formulating the drug as a suspension or a solution in aliquefied gas propellant. The suspension/solution is stored in a sealedcanister capable of withstanding the pressure required to maintain thepropellant as a liquid. The suspension/solution is dispersed byactivation of a dose-metering valve affixed to the canister.

A metering valve generally comprises a metering chamber, which is of aset volume and is designed to administer per actuation an accuratepredetermined dose of medicament. The suspension/solution is forced fromthe dose-metering valve on actuation by the high vapour pressure of thepropellant. The propellant rapidly vaporises leaving a cloud of veryfine particles of the drug formulation. This cloud of particles isdirected into the nose or mouth of the patient by a channelling devicesuch as a cylinder or open-ended cone. Concurrently with the actuationof the aerosol dose-metering valve, the patient inhales the drugparticles into the lungs or nasal cavity. Systems for dispensing drugsin this way are known as “metered dose inhalers” (MDIs). See PeterByron, Respiratory Drug Delivery, CRC Press, Boca Raton, Fla. (1990) fora general background on this form of therapy.

Patients often rely on medication delivered by MDIs for rapid treatmentof respiratory disorders, which are debilitating and in some cases evenlife threatening. Therefore, it is essential that the prescribed dose ofaerosol medication delivered to the patient consistently meets thespecifications claimed by the manufacturer and complies with therequirements of the FDA and other regulatory authorities. That is, everydose delivered from an MDI must lie within a very tightly controlledspecification range.

A problem which can exist with drug delivery devices such as MDIs is thedeposition of the medicament, or the solid component from a suspensionof a particulate product in a liquid propellant, onto the internalsurfaces of the device which can occur either immediately aftermanufacture or after a number of operation cycles and/or storage. Thiscan lead to a reduction in the efficacy of the device and of theresulting treatment as the deposition of the product reduces the amountof active drug available to be dispensed to the patient and can alsoreduce the uniformity of the dose dispensed during the lifetime of thedevice.

The problem of drug adherence and dose uniformity can be greater withsuspension formulations comprising hydrofluoroalkane propellants, forexample, 1,1,1,2-tetrafluoroethane (HFA134a) and1,1,1,2,3,3,3-n-heptafluoropropane (HFA227) which have been developed asozone friendly replacements of chlorofluorocarbon propellants such asP11, P114 and P12.

Some conventional devices rely on shaking the dispenser to agitate theliquid propellant and product mixture therein, in an attempt to dislodgethe deposited particles. However, while in some cases this remedy can beeffective within the body of the drug canister itself, it may not beeffective for particles deposited on the inner surfaces of the other MDIcomponents, such as the metering valve.

One solution to this problem is to provide a coating on the internalsurfaces of the valve or canister which contact the medicament and whichinhibits drug deposition, wherein the coating is of a fluorinatedpolymer, for example PTFE. The process used to date to provide such acoating is a continuous wave radio frequency plasma process, such as acold plasma radio frequency process, which in theory operates in anenergy range of 2 MHz to 200 MHz, but practically is only able tooperate at an energy of 13.56 MHz, 27.12 MHz and 40.68 MHz, since theseare the only frequencies designated to industrial use in unrestrictedpower. There are, however, problems with using such a continuous waveradio frequency plasma process: the substrate and/or monomer may bedamaged by the use of continuous waves of this specific energy andfrequency; the inside of intricate shapes will not be coated or beinsufficiently coated; some of the coating may break free and end up inthe canister along with the drug formulation; and the coating may bedifficult to characterise.

SUMMARY OF THE INVENTION

It is therefore an aim of the present invention to provide a dispenserfor a medicament in which one or more of the surfaces thereof have afluorinated coating provided by a process which does not result in theproblems mentioned above.

A further aim of the invention is to provide a coating which reducesmoisture ingress into a pharmaceutical aerosol formulation, reduces theabsorption of the drug into the substrate, e.g. of rubber, and reducesfriction between movable parts in inhalation devices.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect of the invention there is provided a medicamentdispenser comprising a canister and a drug dispensing valve, wherein oneor more surfaces of said canister and/or valve has a fluorinated coatingprovided by a process comprising generating one or morefluorine-containing radical species and polymerising said radicals onsaid one or more surfaces, provided that the radicals are generated by ahot filament chemical vapour process, pyrolisation of fluoroparylenedimers, use of a photo initiator to create radicals from afluoroacrylate or laser ablation of a fluoropolymer target.

The invention also provides a process for the preparation of amedicament dispenser as hereinbefore defined, said process comprisinggenerating one or more fluorine-containing radical species by (i) a hotfilament chemical vapour process, pyrolisation of fluoroparylene dimers,use of a photo initiator to create radicals from a fluoroacrylate orlaser ablation of a fluoropolymer target, and (ii) polymerising saidradicals on said one or more surfaces. Polymerisation of the radicalsmay occur subsequent to generation of the radicals, or polymerisationmay begin while additional radicals are being generated.

In the case of a hot filament chemical vapour process, a fluorinatedcompound, such as a fluorinated gas, is heated to providefluorine-containing radicals, such as CF₂ radicals, which subsequentlycondense and polymerise on the surface of a substrate to form anessentially PTFE coating. This process is a simple process that can beused to coat intricate substrates and which causes no damage to thesubstrate.

Alternatively, fluoroparylene dimers, for example of formula (I)

are heated and then pyrolised to form a di-radical monomer, whichcondenses and polymerises on a cooled substrate. This is a simpleprocess, which can be used to coat intricate substrates and causes nodamage to the substrate. Furthermore, the composition of the coatingwill be known.

Alternatively, a photo initiator, for example formulaPhCh₂C(OH)(CH₃)CHO, is used to create radicals from a fluoroacrylate,for example of formula C₈F₁₇CH₂CH₂OCO═CH₂. The radicals so formed thenpolymerise on one or more of the surfaces of the canister and/or valve.

Alternatively, fluorinated radicals may be obtained by laser ablation ofa fluoropolymer target. For example, a pulsed laser may be directed ontosintered fluoropolymer, such as PTFE, in an argon atmosphere, thefluoropolymer volatilises to form fluorine-containing radicals, theradicals polymerising on one or more surfaces of the canister and/orvalve.

The invention further provides a medicament dispenser comprising acanister and a drug dispensing valve, wherein one or more surfaces ofsaid canister and/or valve has a fluorinated coating provided by aprocess comprising incorporating a fluorine-containing species into aliquid or gas, depositing a fluorine-containing layer on said one ormore surfaces, and thereafter optionally removing the liquid or gas.

The invention further provides a process for the preparation of amedicament dispenser as hereinbefore defined, said process comprisingincorporating a fluorine-containing species into a liquid or gas,depositing a fluorine-containing layer on said one or more surfaces, andthereafter optionally removing the liquid or gas.

In one embodiment, a fluorine-containing species, such as a fluorinatedpolymer, is dissolved in a supercritical fluid solution, for examplesupercritical CO₂, and subsequently deposited on one or more surfaces ofthe canister and/or valve to form a coating, thereafter removing thesupercritical fluid. Such a process is simple and clean and provides acoating of known composition.

In a further embodiment, a fluorine-containing species, such as afluoropolymer, is dissolved in a solvent, such as ethanol, which doesnot require a high temperature curing process, one or more of thesurfaces of the canister and/or valve are coated, and the solvent issubsequently removed.

In a further embodiment, a nanoemulsion of a fluorine containingspecies, such as a fluoropolymer, for example PTFE, is prepared, theemulsion is applied to the canister and/or valve surfaces to be coatedand is dried, for example at 100° C.

In a yet further embodiment, a fluorine-containing species, for examplefluorine gas, is incorporated into an inert gas at an elevatedtemperature, for example 100° C. Hydrogen atoms at the substrate surfaceare substituted with fluorine atoms to provide a monolayer coating offluorine.

Ordinarily, the surface(s) to be coated is a surface which, in use ofthe dispenser, contacts the medicament, e.g. when the dispenser isfilled with a medicament in a fluid propellant.

One advantage of using a coating process hereinbefore described is thatintricate shapes may be coated and the coating is not restricted to the“line of sight”. That is, the inside of components not readily visiblemay be coated.

Suitably, the surface energy of the resulting coating of the invention,gives a contact angle of greater than 70 degrees, preferably greaterthan 90 degrees, more preferably greater than 110 degrees. The term“contact angle” is the angle between a liquid water droplet and thecoated surface of the canister/valve at the liquid/solid interface asmeasured in ambient conditions, i.e. at a temperature of 20° C. (±5° C.)and a relative humidity of 50% (±20%). The contact angle may be measuredon a coating deposited on a flat polybutylene terephthalate (PBT)substrate surface in accordance with the process of the invention.

In a further embodiment, the dispenser of the invention furthercomprises moisture-absorbing means. The moisture absorbing means willgenerally comprise a desiccant material.

In one embodiment, the moisture absorbing means is contained within thecanister. Preferably, the moisture absorbing means will be particulate,the particles being of a size which are not inhaled into the lung, forexample they have a mean size (e.g. mass median diameter MMD) of greaterthan 100 μm. According to another aspect of this embodiment, preferablythe moisture absorbing means is not able to pass through the valve (e.g.not able to enter the metering chamber of the valve), for example byvirtue of its size. In one example of this arrangement, the moistureabsorbing means is present in the canister as a tablet or bead. In analternative aspect the moisture absorbing means is not able to passthrough the valve because it is attached to the canister.

Examples of moisture absorbing means suitable for use include nylon.Another example is silica gel. Other exemplary moisture absorbing meansinclude inorganic materials such as zeolites, alumina, bauxite,anhydrous calcium sulphate, water-absorbing clay, activated bentoniteclay, a molecular sieve, or other like materials. When nylon is used itis preferably supplemented with use of another desiccant material havinga higher water capacity (such as one of the inorganic materials justmentioned).

The moisture absorbing means should be present in sufficient quantity toabsorb undesired moisture and will typically have a water absorptioncapacity of 20-50 weight percent. Typically 10 μg to 5 g, for example 1mg to 5 g, e.g. 100 mg to 500 mg such as about 100 mg to 250 mg ofmoisture absorbing material should be adequate for a typical metereddose inhaler.

In a further embodiment of the invention, the canister and/or valve ispartially or wholly manufactured of or incorporates a moisture absorbingmeans, suitably a desiccant material. Preferably, the material fromwhich the canister and/or valve is manufactured will be loaded with atleast 5% by weight of the moisture absorbing means, more preferably 10to 80% by weight, especially 20 to 60% by weight. One embodiment is anacetal valve loaded with a desiccant material which is a molecularsieve.

Loading when used in this specification will be understood to includecoating and/or lining. However, desiccant which is loaded may beadsorbed at least in part into the material from which the component ismanufactured.

Preferably, the moisture absorbing means is incorporated within thevalve rather than within the canister.

When the valve is a metering valve comprising a valve body which definesa metering chamber, the moisture absorbing means may, for example, beincorporated within the metering chamber of the valve. For example, themetering chamber may be partially, or preferably, wholly manufactured ofnylon which is a natural desiccant material. Alternatively, the meteringchamber may be coated with a moisture absorbing means.

The moisture absorbing means may instead (or in addition) beincorporated within one or more valve seals. As used herein, “valveseal” includes one or more of the following lower stem seal and/or upperstem seal and gasket seal employed in the valve for sealing purposes,generally composed of elastomeric materials.

In conjunction with the moisture absorbing means, e.g. desiccant, anadditional compound may be added to act as a conduit/channelling agentto increase/optimise the efficiency of the moisture absorptionproperties. Such materials may include compounds such as polyethyleneglycols.

Any parts of the canister and/or valve, which contact the pharmaceuticalaerosol suspension, may be coated with the fluorinated coating of theinvention. Such a coating reduces or eliminates the tendency ofmedicament particles to deposit or precipitate out thereon. Where thevalve part is a movable part (e.g. the valve stem) the coating alsoreduces the friction between that part and another part of the valve(e.g. the stem seal). Accordingly, a further aspect of the inventionprovides a method of preventing drug deposition in a dispenser fordispensing a medicament in a fluid propellant having a canister forhousing the medicament and a drug-dispensing valve, the methodcomprising the use of a dispenser as defined above.

In a further aspect, the invention provides a canister for housing themedicament, wherein one or more of the surfaces of said canistercomprise a fluorinated coating, wherein said coating is prepared by aprocess as hereinbefore described.

Typically, the canister contains a pharmaceutical aerosol formulationcomprising a medicament and a fluorocarbon propellant.

In another aspect, the invention provides a drug-dispensing valve foruse in a dispenser for dispensing a medicament in a fluid propellant,wherein one or more of the surfaces of said valve comprise a fluorinatedcoating, prepared by a process as hereinbefore described.

Typically, the drug-dispensing valve is a drug metering valve.

The valve suitably comprises a number of components or parts, as knownin the art. All may independently of the other components be coated witha fluorinated coating as hereinbefore defined. Component parts of thevalve which may be coated include, but are not limited to, the meteringchamber, valve stem, the upper and lower stem seals, neck gasket, springand body. Suitably, the valve is a metering valve.

Thus another aspect of the invention provides a metering chamber,wherein one or more surfaces thereof comprise a fluorinated coatingaccording to the present invention.

A further aspect of the invention provides a valve stem coated with afluorinated coating according to the present invention. Such a coatingon the valve stem may reduce its frictional contact properties, and theneed for any further stem lubricant such as silicone oil is reduced oreliminated. Reducing frictional contact can be particularly advantageouswhere the valve is employed in a dispenser for both suspension andsolution medicament formulations.

In order to improve adhesion of the fluorinated coating to the one ormore surfaces, the surfaces to be coated may be subjected to apre-treatment step to remove any surface contamination and/or toactivate the surface. Accordingly, a further aspect of the inventionprovides a dispenser comprising a canister for housing the medicamentand a drug dispensing valve, wherein one or more of the internalsurfaces of the canister and/or valve comprises a fluorinated coatingprepared by the process as hereinbefore defined, characterised in thatthe one or more of the internal surfaces of the canister and/or valveare provided with a pre-treatment step to remove surface contaminationand/or to activate the surface. Additionally, there is provided aprocess for the preparation of a medicament dispenser as hereinbeforedefined, said process comprising providing the one or more of theinternal surfaces of the canister and/or valve with a pre-treatment stepto remove surface contamination and/or to activate the surface, followedby providing a fluorinated coating on the one or more internal surfacesof the canister and/or valve, wherein the coating is prepared by aprocess hereinbefore defined.

Where the fluorinated coating is prepared by the formation offluorine-containing radicals and the polymerisation thereof, thepre-treatment may be achieved by for example treatment of the componentswith an etching gas such as oxygen or argon. Preferably, the etching gasis oxygen. In the process, radicals react with the plastic or metalsubstrate; for example the component is exposed to a low pressure oxygenplasma environment which creates polar groups on the components surfacewhich are more conducive to bonding with the coating to be applied.

The pre-treatment step, for example with oxygen, could be carried outunder a range of conditions and duration. However, the Applicant hasfound that the following conditions provide a satisfactorypre-treatment: run time 120 seconds; power 400 W; gas pressure 300mTorr; gas flow 80 cc/min; tumbler speed 35 rpm. It should be noted,however, that the invention is not limited to these conditions and thatany set of conditions used for a pre-treatment step is within the scopeof the invention.

The dispenser as hereinbefore defined is suitably incorporated as partof a “metered dose inhaler” or “MDI”. The term “metered dose inhaler” or“MDI” means a unit comprising a canister, a cap (ferrule) covering themouth of the canister (typically crimped), a drug metering valvesituated in the cap, a metering chamber and a suitable channellingdevice (actuator) into which the canister is fitted. The term “drugmetering valve” or “MDI valve” refers to a valve and its associatedmechanisms which deliver a predetermined amount of drug formulation froman MDI upon each activation. The channelling device may comprise, forexample, an actuating device for the valve and a cylindrical orcone-like passage through which medicament may be delivered from thefilled MDI can via the MDI valve to the nose or mouth of a patient, e.g.a mouthpiece actuator. The relation of the parts of a typical MDI isillustrated in U.S. Pat. No. 5,261,538, the content of which is herebyincorporated herein by reference. The metered dose inhalers may beprepared by methods of the art (e.g. see Byron above and U.S. Pat. No.5,345,980, the contents of which are hereby incorporated herein byreference).

Thus, in another aspect, the invention provides a metered dose inhalerfor dispensing a medicament in a fluid propellant comprising a dispenseras defined above and a medicament channelling device, such as anactuator.

In addition to the canister and the valve being provided with afluorinated coating of the invention, other component parts of the MDImay also be provided with such a coating. Accordingly, a further aspectof the invention provides a ferrule having one or more of its surfacesprovided with a fluorinated coating of the invention. A yet furtheraspect provides an actuator having one or more of its surfaces providedwith a fluorinated coating of the invention.

Suitably, the entire valve or one or more of the valve components aremade of a non-metal material. Suitable non-metals for use in the valveinclude pharmacologically resilient polymers such as acetal, polyamide(e.g. Nylon®), polycarbonate, polyester (e.g. polybutylterephthalate(PBT)), fluorocarbon polymer (e.g. Teflon®) or a combination of thesematerials. Additionally, seals and “O” rings of various materials (e.g.,nitrile rubbers, polyurethane, acetyl resin, fluorocarbon polymers), orother elastomeric materials are employed in and around the valve.Alternatively, the valve is made of metal, for example stainless steel,aluminium, copper, fin plate and any alloys thereof.

The valve can have any suitable configuration. Metal and non-metal partscan be combined to optimise the performance of the valve.

Conventionally, the canisters and caps for use in MDIs are made ofaluminium or an alloy of aluminium although other metals not affected bythe drug formulation, such as stainless steel, an alloy of copper, ortin plate, may be used. An MDI canister may also be fabricated fromglass or plastics. Preferably, however, the MDI canisters and capsemployed in the present invention are made of aluminium or an alloythereof.

The canister is preferably a pressurised container comprising analuminium metal vial having a metering valve disposed therein. While thepressurised container preferably includes a metering valve, other valvesystems are not beyond the scope of the present invention. Other valvesystems include, but are not limited to, wedge gate valve systems,double-disc gate valve systems, globe and angle valve systems, swingcheck valve systems, end cock valve systems, and other like valvesystems, as known in the art. Since the pressurised container ispreferably part of an MDI, the valve design is typically a function ofproviding a predetermined dosage or amount of the drug contained withinthe pressurised container to a user.

The valve typically comprises a valve body having an inlet port throughwhich the pharmaceutical aerosol formulation may enter said valve body,an outlet port through which the pharmaceutical aerosol may exit thevalve body and an open/close mechanism by means of which flow throughsaid outlet port is controllable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

The valve may be a metering valve in which the valve body has a meteringchamber, a sampling chamber and therebetween a second sealing ringwithin which the stem is slidably movable, the valve stem having atransfer passage such that in the valve-closed position the dispensingpassage is isolated from the metering chamber and the metering chamberis in communication with the sampling chamber via the transfer passage,and in the valve-open position the dispensing passage is incommunication with the metering chamber and the transfer passage isisolated from the metering chamber. The metering volumes are typicallyfrom 50 to 100 μl, such as 50 μl or 63 μl.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined therebetween and such that duringmovement between its non-dispensing and dispensing positions the valvestem sequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurised aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurized aerosolformulation. A valve of this type is described in U.S. Pat. No.5,772,085 the content of which is hereby incorporated herein byreference.

The valve may also have a structure and action similar to those aerosolvalves described in European Patent Application No. EP-A-870,699 and PCTPatent Application No. WO99/36334, the contents of which are herebyincorporated herein by reference.

The neck gasket (sealing ring) may be formed by cutting a ring from asheet of suitable material. Alternatively, the neck gasket may be formedby a moulding process such as an injection moulding, a compressionmoulding or a transfer moulding process.

Typically, the neck gasket(s) comprises an elastomeric material. Thering is typically resiliently deformable.

The elastomeric material may either comprise a thermoplastic elastomer(TPE) or a thermoset elastomer, which may optionally be cross-linked.The sealing ring may also comprise a thermoplastic elastomer blend oralloy in which an elastomeric material is dispersed in a thermoplasticmatrix. The elastomers may optionally additionally contain conventionalpolymer additives such as processing aids, colorants, tackifiers,lubricants, silica, talc, or processing oils such as mineral oil insuitable amounts.

Suitable thermoset rubbers include butyl rubbers, chloro-butyl rubbers,bromo-butyl rubbers, nitrile rubbers, silicone rubbers, fluorosiliconerubbers, fluorocarbon rubbers, polysulphide rubbers, polypropylene oxiderubbers, isoprene rubbers, isoprene-isobutene rubbers, isobutylenerubbers or neoprene (polychloroprene) rubbers.

Suitable thermoplastic elastomers comprise a copolymer of about 80 toabout 95 mole percent ethylene and a total of about 5 to about 20 molepercent of one or more comonomers selected from the group consisting of1-butene, 1-hexene, and 1-octene as known in the art. Two or more suchcopolymers may be blended together to form a thermoplastic polymerblend.

Another suitable class of thermoplastic elastomers are thestyrene-ethylene/butylene-styrene block copolymers. These copolymers mayadditionally comprise a polyolefin (e.g. polypropylene) and a siloxane.

Thermoplastic elastomeric material may also be selected from one or moreof the following: polyester rubbers, polyurethane rubbers, ethylenevinyl acetate rubber, styrene butadiene rubber, copolyether ester TPE,olefinic TPE, polyester amide TPE and polyether amide TPE.

Other suitable elastomers include ethylene propylene diene rubber(EPDM). The EPDM may be present on its own or present as part of athermoplastic elastomer blend or alloy, e.g. in the form of particlessubstantially uniformly dispersed in a continuous thermoplastic matrix(e.g. polypropylene or polyethylene). Commercially availablethermoplastic elastomer blend and alloys include the SANTOPRENE™elastomers. Other suitable thermoplastic elastomer blends includebutyl-polyethylene (e.g. in a ratio ranging between about 2:3 and about3:2) and butyl-polypropylene.

Typically, the stem gasket(s) additionally comprises and/or are coatedwith lubricant material.

In addition, the stem may also comprise lubricant material. Suitably,the valve stem comprises up to 30% by weight, preferably from 5 to 20%by weight of lubricant material.

The term ‘lubricant’ herein means any material that reduces frictionbetween the value stem and seal. Suitable lubricants include siliconeoil or a fluorocarbon polymer such as polytetrafluoroethane (PTFE) orfluoroethylene propylene (FEP).

Lubricant can be applied to the stem, or stem gasket(s) by any suitableprocess including coating and impregnation, such as by injection or atamponage process.

In medical use the canisters in accordance with the invention maycontain a pharmaceutical aerosol formulation comprising a medicament anda fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds or mixtures, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons for exampleCHClF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane (CF₃CH₂F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof.

The pharmaceutical formulations for use in the canisters of theinvention contain no components that provoke the degradation ofstratospheric ozone. In particular the formulations are substantiallyfree of chlorofluorocarbons such as CCl ₃ F, CCl ₂F₂ and CF ₃ CCl ₃ .

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, isobutane, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations, which arefree or substantially free of volatile adjuvants are preferred. Incertain cases, it may be desirable to include appropriate amounts ofwater, which can be advantageous in modifying the dielectric propertiesof the propellant.

The invention is particularly useful with propellants (includingpropellant mixtures) which are more hygroscopic than P11, P114 and/orP12 such as HFA-134a and HFA-227.

A polar co-solvent such as C₂₋₆ aliphatic alcohols and polyols e.g.ethanol, isopropanol and propylene glycol, preferably ethanol, may beincluded in the drug formulation in the desired amount to improve thedispersion of the formulation, either as the only excipient or inaddition to other excipients such as surfactants. Suitably, the drugformulation may contain 0.01 to 30% w/w based on the propellant of apolar co-solvent e.g. ethanol, preferably 0.1 to 20% w/w e.g. about 0.1to 15% w/w. In aspects herein, the solvent is added in sufficientquantities to solubilise a part or all of the medicament component, suchformulations being commonly referred to as solution formulations.

A surfactant may also be employed in the aerosol formulation. Examplesof conventional surfactants are disclosed in EP-A-372,777, the contentof which is hereby incorporated herein by reference. The amount ofsurfactant employed is desirable in the range 0.0001% to 50% weight toweight ratio relative to the medicament, in particular, 0.05 to 5%weight to weight ratio.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005 to 5% w/w, especially 0.01 to 1.0% w/w, of medicamentrelative to the total weight of the formulation.

Medicaments, which may be administered in the aerosol formulationsinclude any drug useful in inhalation therapy. The dispenser of theinvention is in one aspect suitable for dispensing medicament for thetreatment of respiratory disorders such as disorders of the lungs andbronchial tracts including asthma and chronic obstructive pulmonarydisorder (COPD). In another aspect, the invention is suitable fordispensing medicament for the treatment of a condition requiringtreatment by the systemic circulation of medicament, for examplemigraine, diabetes, pain relief, e.g. with inhaled morphine.

Accordingly, in one aspect of the invention, there is provided the useof a dispenser or MDI according to the invention for the treatment of arespiratory disorder, such as asthma and COPD. Additionally, the presentinvention provides a method of treating a respiratory disorder such as,for example, asthma and COPD, which comprises administration byinhalation of an effective amount of an aerosol formulation as hereindescribed from a dispenser or MDI of the present invention.

A further aspect of the invention provides the use of a dispenser or MDIaccording to the invention for the treatment of a condition requiringthe systemic circulation of a medicament, such as, for example,migraine, diabetes, chronic pain.

The present invention also provides a method of treating a conditionrequiring the systemic circulation of medicament, such as, for examplemigraine, diabetes and chronic pain, which comprises administration byinhalation of an effective amount of an aerosol formulation as hereindescribed from a dispenser or MDI or the present invention.

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate (e.g. s the sodium salt), ketotifen or nedocromil (e.g. asthe sodium salt); antiinfectives e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. asthe propionate or furoate ester), flunisolide, budesonide, rofleponide,mometasone e.g. as the furoate ester), ciclesonide, triamcinolone (e.g.as the acetonide) or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoic acid (e.g. as free acid orpotassium salt), diuretics, e.g., amiloride; anticholinergics, e.g.,ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium;hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines,e.g., aminophylline, choline theophyllinate, lysine theophyllinate ortheophylline; therapeutic proteins and peptides, e.g., insulin orglucagon; vaccines, diagnostics, and gene therapies. It will be clear toa person skilled in the art that, where appropriate, the medicaments maybe used in the form of salts, (e.g., as alkali metal or amine salts oras acid addition salts) or as esters (e.g., lower alkyl esters) or assolvates (e.g., hydrates) to optimise the activity and/or stability ofthe medicament.

Preferred medicaments are selected from albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (e.g. as the fumarate salt)in combination with an anti-inflammatory steroid such as abeclomethasone ester (e.g., the dipropionate) or a fluticasone ester(e.g., the propionate) or budesonide. A particularly preferredcombination is a combination of fluticasone propionate and salmeterol,or a salt thereof (particularly the xinafoate salt). A furthercombination of particular interest is budesonide and formoterol (e.g. asthe fumarate salt).

Particularly preferred formulations for use in the canisters of thepresent invention comprise a medicament and a C₁₋₄ hydrofluoroalkaneparticularly 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-n-heptafluoropropane or a mixture thereof as propellant.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto a can to form anempty canister. The particulate medicament is added to a charge vesseland liquefied propellant is pressure filled through the charge vesselinto a manufacturing vessel. The drug suspension is mixed beforere-circulation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or“puff”, for example in the range of 2 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1, 2, 3 or 4 puffseach time. Each valve actuation, for example, may deliver 5 μg, 50 μg,100 μg, 200 μg or 250 μg of a medicament. Typically, each filledcanister for use in a metered dose inhaler contains 60, 100, 120 or 200metered doses or puffs of medicament; the dosage of each medicament iseither known or readily ascertainable by those skilled in the art.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto which will be within the ordinary skill of theperson skilled in the art.

1. A medicament dispenser comprising a canister and a drug dispensingvalve, wherein one or more surfaces of said canister and/or valve has afluorinated coating provided by a process comprising generating one ormore fluorine-containing radical species and polymerising said radicalson said one or more surfaces, provided that the radicals are generatedby a hot filament chemical vapour process, or by pyrolisation of afluoroparylene dimer, or by using a photo initiator to create radicalsfrom a fluoroacrylate, or by laser ablation of a fluoropolymer target.2. A medicament dispenser comprising a canister and a drug-dispensingvalve, wherein one or more surfaces of said canister and/or valve has afluorinated coating provided by a process comprising incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 3. A medicament dispenseraccording to claim 2, wherein the fluorine-containing species isincorporated into a supercritical fluid.
 4. A medicament dispenseraccording to claim 2, wherein the fluorine-containing species is afluoropolymer.
 5. A medicament dispenser according to claim 2, whereinthe fluorine-containing species is incorporated into a solvent.
 6. Amedicament dispenser according to claim 5, wherein thefluorine-containing species is a fluoropolymer.
 7. A medicamentdispenser according to claim 2, wherein a nanoemulsion of afluoropolymer is applied to one or more surfaces of the canister and/orvalve.
 8. A medicament dispenser according to claim 2 wherein thefluorine-containing species is incorporated into an inert gas.
 9. Amedicament dispenser according to claim 8, wherein thefluorine-containing species is fluorine gas.
 10. A medicament dispenseraccording to claim 1, wherein the fluorinated coating gives a contactangle of greater than 70 degrees.
 11. A medicament dispenser accordingto claim 1, wherein the dispenser further comprises moisture absorbingmeans.
 12. A medicament dispenser according to claim 11, wherein thecanister and/or valve is partially or wholly manufactured of orincorporates the moisture absorbing means.
 13. A canister for housing amedicament, wherein one or more surfaces of said canister comprises afluorinated coating provided by a process comprising generating one ormore fluorine-containing radical species and polymerising said radicalson said one or more surfaces, provided that the radicals are generatedby a hot filament chemical vapour process, or by pyrolisation of afluoroparylene dimer, or by using a photo initiator to create radicalsfrom a fluoroacrylate, or by laser ablation of a fluoropolymer target.14. A canister for housing a medicament, wherein one or more surfaces ofsaid canister comprises a fluorinated coating provided by a processcomprising incorporating a fluorine-containing species into a liquid orgas, depositing a fluorine-containing layer on said one or moresurfaces, and thereafter optionally removing the liquid or gas.
 15. Adrug-dispensing valve for use in a dispenser for dispensing a medicamentin a fluid propellant, wherein one or more surfaces of said valvecomprise a fluorinated coating provided by a process comprisinggenerating one or more fluorine-containing radical species, polymerisingsaid radicals on said one or more surfaces, provided that the radicalsare generated by a hot filament chemical vapour process, or bypyrolisation of a fluoroparylene dimer, or by using a photo initiator tocreate radicals from a fluoroacrylate, or by laser ablation of afluoropolymer target.
 16. A drug-dispensing valve for use in a dispenserfor dispensing a medicament in a fluid propellant, wherein one or moresurfaces of said valve comprise a fluorinated coating provided by aprocess comprising incorporating a fluorine-containing species into aliquid or gas, depositing a fluorine-containing layer on said one ormore surfaces, and thereafter optionally removing the liquid or gas. 17.A drug-dispensing valve according to claim 15, wherein thedrug-dispensing valve is a drug-metering valve.
 18. A drug-dispensingvalve according to claim 15, wherein the fluorinated coating is providedon one or more valve components selected from the group consisting of ametering chamber, valve stem, upper stem seal, lower stem seal, neckgasket, spring and body.
 19. A drug-dispensing valve according to claim15, wherein the fluorinated coating is provided on one or more surfacesof a metering chamber.
 20. A metering chamber, wherein one or moresurfaces thereof are provided with a fluorinated coating provided by aprocess comprising generating one or more fluorine-containing radicalspecies and polymerising said radicals on said one or more surfaces,provided that the radicals are generated by a hot filament chemicalvapour process, or by pyrolisation of a fluoroparylene dimer, or byusing a photo initiator to create radicals from a fluoroacrylate, or bylaser ablation of a fluoropolymer target.
 21. A metering chamber,wherein one or more surfaces thereof are provided with a fluorinatedcoating provided by a process comprising incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 22. A valve stem, wherein one ormore surfaces thereof are provided with a fluorinated coating providedby a process comprising generating one or more fluorine-containingradical species and polymerising said radicals on said one or moresurfaces, provided that the radicals are generated by a hot filamentchemical vapour process, or by pyrolisation of a fluoroparylene dimer,or by using a photo initiator to create radicals from a fluoroacrylate,or by laser ablation of a fluoropolymer target.
 23. A valve stem,wherein one or more surfaces thereof are provided with a fluorinatedcoating provided by a process comprising incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 24. A medicament dispenseraccording to claim 1, wherein the one or more surfaces are provided witha pre-treatment step prior to being provided with the fluorinatedcoating to remove surface contamination and/or to activate the surface.25. A metered dose inhaler for dispensing a medicament in a fluidpropellant, comprising a dispenser according to claim 1, and amedicament channelling device.
 26. A process for producing a medicamentdispenser according to claim 1, comprising the steps of generating oneor more fluorine-containing radical species by a hot filament chemicalvapour process, or by pyrolisation of a fluoroparylene dimer, or byusing a photo initiator to create radicals from a fluoroacrylate, or bylaser ablation of a fluoropolymer target, and polymerising said radicalson said one or more surfaces.
 27. A process for producing a medicamentdispenser according to claim 2, comprising the steps of incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 28. A method of treating arespiratory disorder in patient comprising: (a) providing a medicamentdispenser according to claim 1 comprising a medicament and (b)administering said medicament to the patient for the treatment of therespiratory disorder.
 29. A method of treating a respiratory disorder,comprising administering by inhalation an effective amount of medicamentin a fluid propellant from a dispenser according to claim
 1. 30. Amethod of treating a condition in a patient requiring systemiccirculation of a medicament comprising: (a) providing a medicamentdispenser according to claim 1 comprising a systemically deliverablemedicament and (b) administering said medicament to the patient.
 31. Amethod of treating a condition requiring systemic circulation of amedicament, comprising administering by inhalation an effective amountof medicament in a fluid propellant from a dispenser according toclaim
 1. 32. A canister according to claim 13, wherein the one or moresurfaces are provided with a pre-treatment step prior to being providedwith the fluorinated coating to remove surface contamination and/or toactivate the surface.
 33. A valve according to claim 15, wherein the oneor more surfaces are provided with a pre-treatment step prior to beingprovided with the fluorinated coating to remove surface contaminationand/or to activate the surface.
 34. A metering chamber according toclaim 20, wherein the one or more surfaces are provided with apre-treatment step prior to being provided with the fluorinated coatingto remove surface contamination and/or to activate the surface.
 35. Avalve stem according to claim 22, wherein the one or more surfaces areprovided with a pre-treatment step prior to being provided with thefluorinated coating to remove surface contamination and/or to activatethe surface.
 36. A process for producing a canister according to claim13, comprising the steps of generating one or more fluorine-containingradical species by a hot filament chemical vapour process, or bypyrolisation of a fluoroparylene dimer, or by using a photo initiator tocreate radicals from a fluoroacrylate, or by laser ablation of afluoropolymer target, and polymerising said radicals on said one or moresurfaces.
 37. A process for producing a valve according to claim 15,comprising the steps of generating one or more fluorine-containingradical species by a hot filament chemical vapour process, or bypyrolisation of a fluoroparylene dimer, or by using a photo initiator tocreate radicals from a fluoroacrylate, or by laser ablation of afluoropolymer target, and polymerising said radicals on said one or moresurfaces.
 38. A process for producing a metering chamber according toclaim 20, comprising the steps of generating one or morefluorine-containing radical species by a hot filament chemical vapourprocess, or by pyrolisation of a fluoroparylene dimer, or by using aphoto initiator to create radicals from a fluoroacrylate, or by laserablation of a fluoropolymer target, and polymerising said radicals onsaid one or more surfaces.
 39. A process for producing a valve stemaccording to claim 22 comprising the steps of generating one or morefluorine-containing radical species by a hot filament chemical vapourprocess, or by pyrolisation of a fluoroparylene dimer, or by using aphoto initiator to create radicals from a fluoroacrylate, or by laserablation of a fluoropolymer target, and polymerising said radicals onsaid one or more surfaces.
 40. A process for producing a canisteraccording to claim 14, comprising the steps of incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 41. A process for producing avalve according to claim 16, comprising the steps of incorporating afluorine-containing species into a liquid or gas, depositing afluorine-containing layer on said one or more surfaces, and thereafteroptionally removing the liquid or gas.
 42. A process for producing ametering chamber according to claim 21 comprising the steps ofincorporating a fluorine-containing species into a liquid or gas,depositing a fluorine-containing layer on said one or more surfaces, andthereafter optionally removing the liquid or gas.
 43. A process forproducing a valve stem according to claim 23 comprising the steps ofincorporating a fluorine-containing species into a liquid or gas,depositing a fluorine-containing layer on said one or more surfaces, andthereafter optionally removing the liquid or gas.
 44. A method oftreating a respiratory disorder in patient comprising: (a) providing ametered dose inhaler according to claim 25 comprising a medicament and(b) administering said medicament to the patient for the treatment ofthe respiratory disorder.
 45. A method of treating a respiratorydisorder, comprising administering by inhalation an effective amount ofmedicament in a fluid propellant from a metered dose inhaler accordingto claim
 25. 46. A method of treating a condition in a patient requiringsystemic circulation of a medicament comprising: (a) providing a metereddose inhaler according to claim 25 comprising a systemically deliverablemedicament and (b) administering said medicament to the patient.
 47. Amethod of treating a condition requiring systemic circulation of amedicament, comprising administering by inhalation an effective amountof medicament in a fluid propellant from a metered dose inhaleraccording to claim 25.